Although cigarette smoking causes the vast majority of lung cancers, most lifetime smokers do not develop this disease. Many studies suggest that women have greater susceptibility than men for lung cancer, and genetic variation in tobacco carcinogen-metabolizing enzymes could explain why only some smokers develop lung cancer and why women may be at a greater risk than men. Recent data from our lab has demonstrated that a polymorphic deletion of a UDP-glucuronosyltransferase, UGT2B17, increases risk for lung cancer exclusively in women (Gallagher ef a/., 2007). This is consistent with the fact that UGT2B17 is a major detoxifier of potent tobacco carcinogens and with the fact that expression of several UGT enzymes, including UGT2B17, are regulated by hormones. The overall hypothesis of this application is that variants in UGT1A genes increase risk for lung cancer and that by using a haplotype approach to comprehensively test all UGT1A variation for genetic association with lung cancer, the risk alleles will be identified. Additionally, hormone-dependent regulation of UGTs may be an important variable resulting in differential risk for lung cancer between sexes. This project will use haplotypes to efficiently and comprehensively evaluate variants in the UGT1A gene cluster for involvement in lung cancer risk and for gender-specific associations with this disease. Prior to these independent studies, the candidate, Dr. Carla Gallagher, together with her primary mentor, Dr. Philip Lazarus, an expert in UGT pharmacogenetics, will complete the picture of the involvement of LJGT1A genes in carcinogen metabolism by evaluating UGT1A5, the only UGT1A gene that has yet to be tested for this activity. In Specific Aim 1, expression, activity against tobacco carcinogens, and functional capacity of coding polymorphisms will be determined for UGT1A5. At the completion of the mentored phase, Dr. Gallagher will train with her co-mentor, Dr. M. Daniele Fallin, in haplotype genetics in preparation for the independent phase. In Specific Aim 2, haplotype association studies of LJGT1A genes and lung cancer risk will be performed, and gender-specific associations will be tested. In Specific Aim 3, the effects of gender on expression and activity of UGT1A enzymes will be examined. This study will enable identification of high-risk individuals for targeted lung cancer screening, intervention, and prevention, and may clarify the gender differences in lung cancer risk for design of gender-specific interventions.